Ulcerative disease of the gastric mucosa is a common and important clinical entity whose etiology is poorly understood. The potent ulcerogen, ethanol, has been employed in both physiologic and morphologic settings using a variety of animal models to identify parameters of injury and to assess subsequent reparative processes. Although the mechanism(s) of ethanol-induced gastric injury is unknown, the most accepted theory proposes that ethanol breaks the gastric mucosal barrier by disrupting the surface epithelial cells and the tight junctions that unite them. Physiological studies have shown that ethanol-induced barrier breaking is accompanied by decreases in transmucosal potential difference, tissue resistance, and short circuit current. Concomitant morphologic studies show that ethanol induces extensive necrosis of the gastric surface epithelial cells and substantial injury to the connective tissue compartment, also known as the extracellular matrix. To date, the role of the gastric extracellular matrix in modulating ethanol injury and subsequent repair has received little attention even though such relationships have been established using other tissue models of injury and repair. In this grant proposal, we will employ a variety of morphologic and physiologic techniques to characterize the normal gastric extracellular matrix including the mucosal basement membrane and interstitial matrix. Light, scanning, and transmission electron microscopy, and immunohistochemistry will be used for in vivo and in vitro studies to characterize this connective tissue compartment. In addition, the effects of acute and chronic alcohol on the gastric extracellular matrix will be assessed using identical techniques. Further, the role of the extracellular matrix in the process of mucosal repair will be studied and the effect of synthetic and natural prostaglandins in protecting and/or stabilizing the connective tissue subsequent to ethanol exposure will be assessed. The studies outlined in the proposal should greatly increase our understanding of the mechanisms by which ethanol injures the gastric mucosa, how repair is initiated, and how injury is lessened or prevented.